A compelling argument for developing new strategies to treat oral/head and neck cancer is that its survival rate has not improved significantly in the last 20 years, despite all of the technological advances. Our goal is to develop gene therapy with the Herpes Simplex Thymidine Kinase (HSV-TK) gene in an adenoviral vector and ganciclovir to treat this disease. Our preliminary results with a human cancer in nude mice (the xenograft model) suggest that this system may be an important alternative for treatment. Our specific aims are: Aim l- To determine if gene therapy with the HSV-TK/ganciclovir system reduces the tumor volume of human head and neck squamous cell carcinoma in the xenograft model. The behavior of the tumor volume during the treatment will be compared in animals treated with the HSV-TK/ganciclovir system and in controls. Aim 2-To determine if reduction of the tumor volume can be improved by a) increasing the number of viral particles per tumor volume. b) repeating the treatment, and, c) if repeating the treatment is better, if shorter intervals between administrations (9 days) are more efficient than long intervals (18 and 27 days) to reduce the tumor volume in the xenograft model. The goal is to optimize these variables as a guide for the treatment in humans. We plan on using the information from these experiments for developing a phase I clinical trial in the near future. We are also working on methods to follow this treatment on the molecular level